[go: up one dir, main page]

WO1989004646A1 - Materiaux de reparation des os et administration de medicaments retardee - Google Patents

Materiaux de reparation des os et administration de medicaments retardee Download PDF

Info

Publication number
WO1989004646A1
WO1989004646A1 PCT/US1988/003932 US8803932W WO8904646A1 WO 1989004646 A1 WO1989004646 A1 WO 1989004646A1 US 8803932 W US8803932 W US 8803932W WO 8904646 A1 WO8904646 A1 WO 8904646A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
bone
collagen
mixture
repair material
Prior art date
Application number
PCT/US1988/003932
Other languages
English (en)
Inventor
Steven R. Jefferies
Original Assignee
Jefferies Steven R
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jefferies Steven R filed Critical Jefferies Steven R
Publication of WO1989004646A1 publication Critical patent/WO1989004646A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/3645—Connective tissue
    • A61L27/365—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2817—Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/30—Joints
    • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30667—Features concerning an interaction with the environment or a particular use of the prosthesis
    • A61F2002/30677—Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005—The prosthesis being constructed from a particular material
    • A61F2310/00365—Proteins; Polypeptides; Degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to bone repair materials with improved cohesive and physical strength for ' use in stress-bearing defects or where the ability to produce and maintain the specific shape of an implant is important.
  • the principle of creating a stable interface and conjugate between a protein-based particle and an organic matrix is also applicable to drug delivery materials and devices.
  • the repair of osseous defects involves either non-reso ' rbable or resorbable prosthetic structures.
  • the resorbable structures or materials either support the ingrowth of adjacent bone and soft tissue or actively induce the formation of new bone.
  • This active formation of new bone termed osteoinduction, occurs only in the presence of demineralized bone matrix or in the presence of protein extracts from such matrix, or a combination of both materials.
  • Particles or powders produced from demineralized bone matrix possess greater osteogenic potential per unit weight due to their increased surface area, than blocks or whole segments of demineralized bone.
  • Other method of repairing damaged or missing osseous tissue or bone have also been explored.
  • nonresorbable materials such as biocompatible metals, ceramics, or composite metal-ceramic materials
  • Some of these materials can promote osteocoinduction at their surface, thus leading to a stable, continuous interface with bone.
  • Caffessee et al Journal of Periodontology, Feb 1987 utilizing a "window" implantation technique established that nonabsorbable ceramics, such as hydroxyapatite, fail to stimulate tissue, even when placed in osseous defects.
  • Resorbable ceramics such as tricalcium phosphate, display better conduction of mineralized tissue into.the resorbing graft material when placed in osseous defects.
  • Thiele, et al. in U.S. Patent 4,172,128, recites a process of degrading and regenerating bone and tooth material and products. This process involves first demineralizing bone or dentin, converting the demineralized material into a ucopolysaccharide-free colloidal solution by extraction with sodium hydroxide adding to the resultant solution a physiologically inert foreign mucopolysaccharide, gelling the solution, and then remineralizing the resulting gel.
  • Thiele et al indicate this material to be biocompatible and totally resorbable, thus replaced by body tissue as determined by histiologic analysis the gel material produced by this process is reported to completely replace destroyed bone sections created in experimental animals .
  • the patentees do not indicate any ability by the material to induce new bone. The ultimate fate of these materials in-vivo, or their ability to stimulate the formation of new bone in non-osseous implant sites is not described. The patentees do not describe or quantify the strength properties of these material. Nevertheless, since they are described as gels, one can assume their strength to be low.
  • Urist In U.S. Patent 4,294,753, describes a process of extracting and solubilizing a Bone Morphogenetic Protein (BMP) .
  • BMP Bone Morphogenetic Protein
  • This partially purified glycoprotein which is derived from demineralized bone matrix by extraction, is lyophilized in the form of a powder.
  • Urist describes the actual delivery of BMP in in-vivo testing via direct implantation of the powder, implantation of the powder contained within a diffusion chamber, or coprecipitation of the BMP with calcium, phosphate.
  • Urist describes the induction of new bone after the implantation of one of these forms of BMP in either osseous or non-osseous sites, Urist fails to address the intrinsic physical strength properties of any of these delivery forms. Lyophilized powders and calcium phosphate precipitates, however, possess little if any, physical strength. Furthermore, more recent investigators (see aforementioned Yamazasaki, et al) indicate that calcium phosphate ceramics, such as tricalcium phosphate and hydroxyapatite, when present in high concentrations relative to the BMP present, may actually inhibit the osteogenic action of the BMP. Jefferies in U.S. Patent Nos.
  • 4,394,370 and 4,472,840 describes bone graft materials composed of collagen and demineralized bone matrix, collagen and extracted Bone Morphogenetic Proteins (BMP) . Also described is a com- bination collagen, demineralized bone matrix, plus extracted bone morphogenetic proteins.
  • BMP Bone Morphogenetic Proteins
  • Jefferies describes an anhydrous lyophilized sponge conjugate made from these compositions which when implanted in osseous and non-osseous sites, is able to induce the formation of new bone.
  • the physical strength of these sponges is not specified in the disclosure, however, reports of the compressive strength of other collagen sponges indicates these materials to be very weak and easily compressible (much less then 1 kiliogram load needed to affect significant physical strain in compression or tension) . Smestad in U.S.
  • Patent No. 4,430,760 assigned to Collagen Corporation describes a nonstress-bearing implantable bone prosthesis consisting of demineralized bone or dentin placed within a collagen tube or container. As the patentee indicates, this bone prosthesis can not be used in stress-bearing locatons clinically.
  • Glowacki et al. in U.S. Patent 4,440,7550 apparently assigned to Collagen Corporation and Harvard University describe plastic dispersions of aqueous collagen mixed with demineralized bone particles for use in inducing bone in osseous defects.
  • This graft material as described exists in a gel state and possesses little physical strength of its own. Its use, therefore, must be restricted to defects which can maintain sufficient form and strength throughout the healing process.
  • the demineralized bone particle suspended within the aqueous collagen sol-gel begin to settle under gravitational forces, thus producing an nonhomogeneous or stratified graft material.
  • Seyedin, et al. in U.S. Patent 4,434,094, describes the purification of a protein factor, which is claimed to be different than Urist' s BMP molecule, responsible for the induction of chondrogenic activity.
  • Ries, et al. , in U.S. Paent 4,623,553, describes a method for producing a bone substitute material consisting of collagen and hydroxyapatite and and partially crosslinked with a suitable crosslinking agent, such as glutaraldehyde or formaldehyde.
  • a suitable crosslinking agent such as glutaraldehyde or formaldehyde.
  • the order to addition of these agents is such that the crosslinking agent is added to- the aqueous collagen dispersion prior to the addition of the hydroxyapatite or calcium phosphate particulate material.
  • the resultant dispersion is mixed and lyophilized.
  • the patent lacks any well known components which are known osteogenic inducers, such as demineralized bone matrix or extracted bone proteins.
  • Caplan, et al. in U.S. Patent 4,620,327, describes a method for treating implants such as biodegradable masses, xenogenic bony implants, allografts, and prosthetic devices with soluble bone protein to enhance or stimulate new cartilage or bone formation. These structures may then be crosslinked to immobilize the soluble bone protein or retard its release. While the osteogenic activity of these implants are described in detail, their physical strength is not mentioned.
  • the ability to orient protein or peptide particles in a stable fashion within organic or natural polymeric matrixes permits the ability to release druges, bioactiveproteins, and bioactive peptides in a controlled fashion.
  • compositions which contain demineralized bone matrix particles or conjugates of inorganic particles plus reconstituted structural or matrix proteins exhibit poor physical stability or physical strength when subjected to loads of any magnitude. Furthermore, due to the poor structural integrity of these materials, further processing into alternative shapes or sizes for actual clinical use to induce new bone formation in osseous defects is limited.
  • One of the major objects of this invention is to describe a method ' of producing an osteogenic, biocompatible, composite which possesses unique strength properties. While many disclosures in the art describe the use of crosslinking agents to enhance the physical integrity of protein-based, conjugate, osteoinductive materials, this disclosure documents a precise method and procedure application which produces osteogenic graft materials of exceptional strength and physical integrity.
  • the basic concept described in this application may be adapted to create conjugates of natural biopolymers and inorganic bone minerals which display exceptional bonds between the inorganic particles and the polymeric matrix.
  • the spacial stability of these particles is critical to their successful use clinically.
  • a further objective is the creation of protein based structures which may release drugs or other agents in a controlled and stable fashion.
  • the dimensional and physical stability of these conjugate material plays a significant role in the pharmacologic release properties of these materials. Hence, the physical strength and drug delivery capabilities are interrelated.
  • the surface activation and partial crosslinking of the proteinaeous particles forms a reactive interface such that these particles bind in a stable fashion to the organic matrix, i.e. reconstituted collagen. This step is important with respect to enhanced physical properties.
  • inorganic particles may be bound to and stabilized within an organic or protein-based polymer by first creating a bound interface of calcium-binding protein or peptide to the particle. The modified particle is then bound- to the matrix proteins via chemical crosslinking or activation methods. This method, as in the first case, significantly enhances the physical properties of these conjugates.
  • the primary of object of this application are:
  • particles which contain protein or a ino acid components such as protein microcapsules, finely divided particles of reconstituted collagen, demineralized bone matrix, or demineralized bone matrix extracted in chaotropic agents are partially crosslinked in a low concentration solution of glutaraldehyde, the surface of these particles become highly reactive, thus allowing an increased degree of bonding between the particle and an organic matrix or polymer, in which the particles may be dispersed.
  • These structures when dehydrated into a solid mass, display internal cohesive strength properties not found in simple combinations of the particles dispersed within the matrix component. If the glutaraldehyde is added directly to the matrix prior to addition of the particles and subsequent dehydration, very low levels of cohesive strength are developed.
  • the critical element to increasing the strength and internal cohesiveness protein-based particle/biopolymer matrix conjugated appears to be the partial crosslinking or surface activation of only the particles prior to complexation with the biopolymer organic matrix.
  • the conditions of surface activation and partial crosslink ⁇ ing are material.
  • crosslinking of demineralized bone particles above .25 weight percent glutaraldehyde destroys most of the osteoinductive capacity of the particles.
  • the particles will mineralized by the uptake of calcium phos ⁇ phate, but will not induce new bone.
  • glutaraldehyde above .25 weight percent and, preferrably, below .1 weight percent is a material condition in this invention.
  • reconstituted collagen provides a matrix which demonstrates the unique and unexpected strength properties of this material.
  • the method in which the collagen is reconstituted can have a direct effect on the magnitude of the increased cohesive strength. This will be illustrated in the Examples which follow.
  • Agents other than glutaraldehyde may be used to enhance the surface binding of protein-based particles within a biocompatible matrix.
  • free and available carboxyl groups on the protein particle may be converted to amine groups via reaction with a water soluble carbodiimide in the presence of a diamine. These additional available amine groups can then react with glutaraldehyde in the partial crosslinking reaction.
  • demineralized bone matrix particles can be immersed in solutions of tetracycline which, will enhance binding an organic biopolymer matrix.
  • bone particles or partially demineralized bone particles may be demineralized in solutions of tetracycline.
  • Particles with inorganic components may be added to these osteogenic stress-bearing compositions, provided these particle makeup no more than twenty percent of the total weight of the particles.
  • These inorganic component particles are bound to the biopolymeric organic matrix via functional molecules with calcium or hydroxyapatite binding functionality.
  • all the particles may be inorganic in nature and bound to the matrix in this fashion.
  • the advantage here is enhanced strength as well as limiting the loss of particles from the matrix itself.
  • the increased binding between the particle and matrix constituents can also be advantageous in drug delivery.
  • the method of dispersing a drug, protein, or peptide within the particle prior to crosslinking and surface activation permits the use of drug containing particles with reduced solubility to act as drug reservoirs within a biocompatible matrix.
  • the nature of matrix can regulate the rate of drug release from the conjugate material.
  • the matrix biopolymer can be modified in a number of ways.
  • the hydrophilic or hydrophobic nature of the matrix may be altered by the addition of carbohy ⁇ drates or lipids.
  • the addition of acidic phospholipids to the matrix enhances the calcium binding capacity of the matrix.
  • Additional macromolecules may be added to the matrix to achieve a particular biologic response.
  • the addition of calcium hydroxide whether in a soluble form or as part of an protein-based particle, was found to increase the pH of matrix such that in-vitro bone collagen synthesis was increased in such an environment. Heparin may also be added.
  • crosslinking agents may be added to the • matrix or subjected to the entire conjugate to further retard the degradation of the matrix and decrease its solubility.
  • the degree of matrix degradation and its inflammatory response can also be controlled by the sta- bilizing affect of alkaline phosphatase.
  • compositions are their ability to be cast into definite shapes with good registration of surface detail. Due to their structure, there is much greater informity in these compositions than is found in allogenic tissue. Furthermore a significant fining is the ability of these conjugate structures to be ground or milled by conventional means without gross break ⁇ down of the entire matrix or the development of severe surface defects. This finding is significant since diagnostic techniques now allow the accurate three-dimensional representation of bony defects with the resultant milling of a graft material via CAD/CAM technology. There is no other processed, truely osteogenic, graft material which can be ground to precise specifications for insertion in a bony defect.
  • EXAMPLE ONE Ten grams of demineralized bone matrix are milled in an A-10 mill to a uniform particle size ranging from 75 to 400 microns. The demineralized bone matrix particles are sieved to eliminate particles above 400 microns. Controlling the concentration of glutaraldehyde is material to maintaining sufficient osteoinductive activity of demineralized bone matrix particles. For example, glutaraldehyde crosslinking solutions of as low as 1.0 to 1.5 weight percent can reduce the residual osteoinductive activity of demineralized bone matrix to 10% or less.
  • Glutaraldehyde crosslinking in aldehyde concentrations of .08 to 0.2 weight percent only reduce the residual osteoinductive activity of demineralized bone matrix by 30 35 percent, leaving from a background osteoinductive activity of from 65 to 70 percent of uncrosslinked demineralized bone matrix particles. Therefore, control of the glutaraldehyde concentration used in this procedure is material to maintaining the biologic activity of processed demineralized bone matrix particles.
  • the range of glutaraldehyde used to partially crosslink and surface activate the demineralized bone matrix particle may range from .002 to .25 weight percent glutaraldehyde. The preferred range is from .005 to .09 weight percent glutaraldehyde.
  • the partial crosslinking of demineralized bone matrix retards the resorption of the matrix in a non-inflammatory fashion, enhances the attach ⁇ ment of plasma proteins to the surface of demineralized bone matrix, and facilitates the attachment of the demineralized bone matrix to the organic collagen matrix of the bony surface of the osseous defect.
  • the demineralized bone particles are immersed in a .05 weight percent glutaraldehyde aqueous solution buffered with phosphate buffer to a pH of from 7.0 to 7.6.
  • the glutaraldehyde solution is made isotonic by adding NaCl to a final concentration of approximately 0.9 weight percent.
  • the glutaraldehyde solution may be buffered in the acid or the alkaline range.
  • the glutaraldehyde solution may also be unbuffered consisting of only sterile distilled deionized water or sterile isotonic saline.
  • the demineralized bone matrix (DBM) particles are immersed in the solution of .05 weight percent glutaraldehyde in neutral phosphate buffered isotonic saline for 12 hours with constant agitation at 4 degrees centigrade. At the end of the incubation period, the particles are filtered from the crosslinking solution and washed particles are filtered from the crosslinking solution and washed once with phosphate-buffered isotonic saline.
  • the DBM particles prepared are dried under sterile conditions and then sterilized by an appropriate method, such as ethylene oxide, gamma radiation, or electron beam sterilization.
  • These activated particle may be placed directly in an osseous defect or alternatively, complex with an organic biopolymer as described in later Examples.
  • EXAMPLE TWO The demineralized bone matrix particles are extracted with a chaotropic agent to remove all bioactive or immunologic elements. Allogenic or heterogenic particles treated in this fashion make excellent delivery particles for the complexation of drugs, peptides, or proteins. After swelling in acid or alkaline solutions the extracted demineralized bone particles are immersed in the agent to be bound and released from the particle. The particle is then dried and crosslinked in a controlled fashion as described in Example One. The specific illustration below describes the use of this method.
  • the extracted demineralized bone matrix particles are removed from the extraction solution by vacuum filtration or centrifugation at 800 to 1000 rpm.
  • the extracted demineralized bone matrix particles (EDBMP) are washed 10 to 20 times with neutral sterile phosphate buffered saline. The particles are then dialyzed against several changes of neutral phosphate buffered saline to remove any remaining amounts of the chaotropic agent.
  • a suitable bioactive peptide or protein may be absorbed onto EDMB particles.
  • thyrocalcitonin is used in this fashion.
  • a one gram frac- tion of the EDBM particles are immersed in a 100 ppm so ⁇ lution of thyrocalcitonin in sterile normal saline. The particles are maintained in this solution for 24 to 72 hours with periodic gentle agitation.
  • the complex EDBM-thyrocalcitonin particles are separated by vacuum filtration and rinsed once to remove any excess peptide.
  • the EDMB-thyrocalcitonin particles are immersed in a low concentration glutaraldehyde crosslinking solution as described Example One.
  • the particles are dried and sterilized as describe in that example. When tested in-vitro and in-vivo, particles showed a time dependent release of the peptide.
  • peptides and proteins such as Bone Morphogentic Protein, Insulin-like growth factor.
  • Epidermal Growth Factor, Nerve Growth Factor, Human Growth Hormone, Bovine Growth Hormone, or Porcine Growth Hormone are several examples of peptides or proteins that can be carried by the EDBM matrix particles.
  • Conventional drugs such as tetracycline or other antibiotics, may also be delivered via this system.
  • Protein-based microcapsules can be fabricated and then partially crosslinked under controlled conditions so that they become reactive and bind to an organic biopolymer matrix under controlled conditions.
  • a gelatin-protein microcapsule is fabricated and partially crosslinked to surface activate the microcapsule.
  • microspheres so obtained are then crosslinked as described in Example One.
  • the micro- spheres are crosslinked in .03 weight percent glutaraldehyde in neutral phosphate buffered isotonic saline.
  • the microspheres " are filtered by vacuum filtration and rinsed once with neutral sterile isotonic saline.
  • the spheres are dehydrated and stored dry.
  • the spheres may be co plexed with an organic biopolymer matrix to form a stress-bearing bioprosthesis.
  • the particles are immersed in a 10 micrograms per milliliter solution of tetracycline HCl for from 1 to 24 hours at 4 degrees centigrade. At the end of the immersion period, the particles are rinsed once in neutral buffered isotonic saline. The particles are collected and dried or lyophilized. The particles in this instance are collected, dried under ambient conditions and lyophilized. As an additional procedure, the dried particles are partially crosslinked with glutaraldehyde as described in Example One. As will be described in Example 6, these tetracycline treated demineralized bone matrix particles are subjected to other means of chemical group activation such as via carbodiimide activation of surface carboxyl groups and reaction with an amine or diamine.
  • EXAMPLE FIVE .Other protein containing particles are fabricated from pulverized reconstituted collagen particles.
  • collagen-tetracycline conjugates sponges are fabricated by adding tetracycline HCl to an acid solubilized reconstituted collagen dispersion.
  • the final tetracycline concentration is 10 to 50 micrograms per milliliter and the collagen concentration is from a .5 weight percent dispersion to a 3.5 weight percent dispersion.
  • the collagen is solubilized with acetate or hydrochloric acid in the acid range or sodium hydroxide in the alkaline range.
  • the pH of the collagen dispersion is adjusted to neutrality or near neutrality by repeated dialysis against sterile distilled water or phosphate buffered saline.
  • the appropriate drug, peptide, or protein is added to the collagen dispersion and agitated to assure complete mixing.
  • the collagen-tetracycline composition is poured into a cylindrical mold and allowed to stand for 24 hours in a sterile laminar flow box to allow initial gellation.
  • the dispersion is placed on the minus 60 degree shelf of a lyophilizer and freeze-dried to form a sponge material.
  • the sponge conju ⁇ gate material is removed from the lyophilizer and placed in a controlled dry-heat oven at a temperature of form 45 to 80 degrees centigrade.
  • the heat stability of the molecule conjugated to the collagen determines the appropriate temperature.
  • the dried sponge is removed and milled to a powder in an A-20 mill.
  • the collagen-tetracycline particles produced are then surface activated and partially cross linked.
  • EXAMPLE SIX The binding and covalent attachment of protein-based particles protein microcapsules, demineralized bone matrix particles, or protein conjugated inorganic particles, are enhance by increasing the number of surface binding sites. This increase in binding sites accomplished by the following procedure.
  • 0.05 molar to about 0.1 molar preferably about 0.05 molar in a isotonic salt solution The pH of the carbodiimide solution was maintained between about 4.7 and about 5.2 by the addition of HCl. Ethanol and other organic compounds, such as mannitol are added from time to time to alter the dielectric constant of the crosslinking ' solution. Alternatively, the ionic strength is increased by the addition of NaCl from about .1 molar to 1.0 molar. Similar modification is undertaken from time to time with the glutaraldehyde crosslinking procedures.
  • the reaction with the carbodiimide proceeds from about 20 minutes up to 12 hours or more.
  • the reaction time is 2 hours and the reaction is carried out at four °C, the surface activated demineralized bone particles are then contacted with an amine or diamine.
  • Materials with amine functional groups include amino acids, polyamino acids, globular proteins such as albumin and gelatin, fibrillar proteins such as collagen and elastin.
  • a diamine namely hexanediamine, is used to react with the carbodiimide activated particles.
  • the hexanediamine permits the increase of free available amine binding sites for activation by glutaraldehyde.
  • the hexanediamine solution contains from .01 weight percent to about 2.0 weight percent diamine.
  • the optimal diamine concentration is approximately .1 to .5 weight percent in a neutral buffered saline solution at pH 7.4.
  • the contact time is from 2 to 10 hours with the usual time being four hours.
  • the particles are removed from the diamine solution by filtration and are rinsed several times with neutral buffered saline to remove excess diamine.
  • the demineralized bone particles are added to a crosslinking solution of glutaraldehyde with an aldehyde concentration of from .001 weight percent to .25 weight percent.
  • the method used is identical to Example One and the concentration of glutaraldehyde is .05 weight percent.
  • the partial crosslinking occurs at 4 °C in a neutral buffered isotonic saline solution.
  • the crosslinking solution time is 8 to 12 hours.
  • the particles filterd from the solution and are washed once with buffered neutral isotonic saline.
  • the particles are dried and at this point can be used for binding in an organic biopolymer matrix to produce a stress-bearing bone graft, as described herein.
  • the particles are lyophilized and sterilized by either ethylene oxide, liquid sterilizing solution, gamma radiation, or electron beam sterilization.
  • aqueous collagen dispersion is made from a high purity, medical grade, sterile powdered collagen.
  • the constituted collagen dispersion is made at 2.5 weight percent collagen by solubilizing the collagen powder in a .01 N acetic acid buffer.
  • the collagen powder is added, from time to time in concentrations ranging from 0.5 weight percent to 2.5 weight percent,
  • Other organic acids, such as lactic acid or inorganic acids, such as hydrochloric acid are also used from time to time to facilitate the swelling of the collagen matrix.
  • the acid dispersion of the collagen is mixed with moderate agitation and stored overnight to permit thorough swelling of the collagen gel.
  • the collagen dispersion is vigorously agitated and sheared in a Waring Blender under medium to high speed using 3 to 5 intermittant, 30 second mixing periods.
  • the collagen dispersion is then poured into an appropriately sized centrifuge tubes and centrifuged at 800 rpm to remove entrained air within the collagen dispersion.
  • the dispersion is then dialyzed against a solution of sterile distilled water.
  • the collagen dispersion is repeatedly dialyzed against fresh exchanges of sterile distilled water until the pH of the collagen dispersion is in the range of pH 5.3 to 7.0.
  • the collagen dispersion is dialyzed against a buffer solution such as neutral phosphate buffer.
  • the dialyzed collagen dispersion is collected and placed in a container at 4 degrees centigrade.
  • the dispersion serves as a matrix material.
  • the first type are normal demineralized bone particles without surface activation with glutaraldehyde.
  • the second type are particles of demineralized bone matrix identical to the first group except they are activated by partial crosslinking in glutaraldehyde as described in Example One.
  • These two systems are described as follows: 1) Demineralized bone particles at 85 weight percent are dispersed in the aqueous collagen matrix; placed " in a cylindrical mold and cast by forced air dehydration at ambient conditions. The conjugate cylinders are retained for physical testing. 2) Demineralized bone particles, identical to above (1) , are activated in glutaraldehyde as described in Example One. These particles are then dispersed at 85 weight percent in the aqueous collagen matrix. the conju ⁇ gate is placed in a cylindrical mold and cast by forced air dehydration at ambient conditions. The conjugate cylinders are retained for physical testing.
  • Demineralized bone particles at 85 weight percent are dispersed in the collagen matrix.
  • Neutral buffered glutaraldehyde is added to the aqueous dispersion so that the final concentration is 0.5 weight percent.
  • the conjugate is placed in a cylindrical mold and cast by forced air dehydration at ambient conditions. The conjugate cylinders are retained for physical testing.
  • Neutral buffered glutaraldehyde is added to the collagen dispersion prior to the addition of demineralized bone matrix particles (unactivated) .
  • the glutaraldehyde is added so that its concentration with respect to the total weight of the conjugate would be 0.5 weight percent.
  • the demineralized bone matrix particles are then added with mixing at a weight ratio of 85 weight percent.
  • conjugate is placed in a cylindrical mold and cast by forced air dehydration at ambient conditions .
  • the conjugate cylinders are retained for physical testing.
  • Conjugate cylinders are fabricated as described for System (1) above, but are then immersed in a neutral
  • Collagen-demineralized bone particle compositions at or above 90 weight percent bone particles to collagen fail to aggregate into a cohesive mass and spontaneous disintegrate under any degree of force.
  • EXAMPLE EIGHT The nature of the matrix biopolymer also has a definite effect on the internal cohesive strength of the material and its ultimate strength properties.
  • the proce- dure below illustrates the fabrication of a collagen-based material which is adhesive to itself or other bone composi ⁇ tions, is hemostatic, and is osteogenic.
  • the collagen mixture is transferred to dialysis tubing (Spectrapor. 12,000 to 14,000 molecular weight cut-off) and dialyzed overnite against sodium phosphate buffer .02 molar pH 7.4.
  • the collagen-DBP dispersion is removed from the dialysis tubing using aseptic technique. The dispersion is homogeneous and shows no evidence of separation.
  • the pH of the dialyzing solution is 6.5.
  • the pH of the collagen dispersion was 5.00 to 5.12.
  • the dialyzed collagen-DBP dispersion is collected, placed in a 250 milliliter centrifuge bottle, then spun at 800 rp for 10 minutes. The clear supernatant is collected and checked for pH and checked for pH, which is 5.10.
  • the collagen-DBP dispersion is placed in sterile petri dishes and frozen, under aseptic conditions, at minus 40°C under vacuum, the vacuum is maintained for 18 to 24 hours to assure complete dehydration.
  • the resultant foam-like sponge material is placed in an A-10 mill and milled into a powder.
  • the powder is divided into equal aliquots and bottled.
  • the bottles of collagen-DBP powder are sterilized under ethylene oxide for 2 and 1/2 hours.
  • the bottles are aerated under vacuum for at least 24 hours and then sealed under vacuum.
  • the resultant material is hemostatic in that it promotes the clotting of blood.
  • EXAMPLE NINE The collagen-demineralized bone • particle powder, as described in Example Eight is reconstituted in a 5 mM solution of, sodium phosphate buffer, pH 8.0. Approximately .2 grams of the powder is hydrated with 1 milliliter of the buffer and mixed to assure complete mixing. Demineralized bone particles, average particle size 250 microns are activated and partially crosslinked as described in Example One. A weight of .10 grams of these particles are added to the buffer-collagen conjugate dispersion with gentle mixing. The mixture is placed in a cylindrical mold and dehydrated by forced air under ambient conditions. The resultant disc dried very rapidly, i.e., within 4 to 10 hours. If the mass is lyophilized, a more porous structure results.
  • EXAMPLE TEN Other drugs, proteins, or peptides are added to the matrix phase of these compositions which contain activated particles.
  • activated particles For example, a purified or recombinant bone morphogenetic protein, as described by Urist in U.S. Patent 4,294,753 is added to the matrix prior to the addition of activated particles or microcapsules.
  • the conjugate material can be used in its aqueous form, however, in this instance the activated demineralized bone particles-collagen-BMP conju ⁇ gate is dehydrated under ambient conditions, as described earlier. Another sample is dehydrated and then lyophilized at minus 40 to minus 60 degrees centigrade.
  • Another conjugate made in identical fashion with respect to order of addition of components, consist of activated demineralized bone particles-collagen and tetracycline HCL. This conjugate is dehydrated and lyophilized. Other proteins and peptide growth factors are evaluated when complexed with the matrix phase of this novel, cohesive compositions.
  • EXAMPLE ELEVEN The activated and partially crosslinked protein particles, microcapsules or demineralized bone matrix particles whose methods of surface activation were described in above Examples, are added to viscous mixtures of blood proteins, glycoproteins, or cell component fractions.
  • activated demineralized bone matrix or bone matrix particles are removed from the container in which they are sterilized.
  • the bone is being used to fill an osseous defect in a laboratory animal.
  • Five milliliters of the animal's blood is withdrawn by ventipuncture.
  • the blood is spun at 800 to 1000 rpm in a table-top centrifuge to spin-down platelets, white blood cells and red blood cells.
  • the blood is drawn into a plain vial which does not contain any type of anticoagulant.
  • the supernatant containing serum is withdrawn carefully with a pipette.
  • the serum is added to the ac- tivated demineralized bone particles so that the particles are evenly coated.
  • the ratio of activated bone particle to serum or plasma can vary from 20 to 95 percent by weight.
  • the conjugate is placed into the bony defect such that it is filled completely. The defect is gradually replaced with new bone over a period of 6 to 12 weeks.
  • Rabbit bone morphogenetic protein is purified from rabbit demineralized bone matrix, using a method described by Urist in U.S.
  • Patent 4,294,753 The purified BMP is added to the plasma so as to constitute about .5 to 3 percent by weight. After mixing the lyophilized protein into the plasma and dispersing it thoroughly, the activated demineralized bone particles are mixed into the BMP-plasma at a weight ratio of 80 to 90 parts of particles to 10 to 20 parts of plasma. Another laboratory animal presented with a bone injury with possible bacterial contamination. Blood is drawn and plasma obtained as previously mentioned. To the plasma is added a powder tetracycline hydrochloride salt at a concentration of 5 to 25 micrograms per milliliter. The antibiotic is mixed thoroughly in the plasma and the plasma mixed with activated demineralized bone particles at a weight ratio of 80 to 90 parts particles to 10 to 20 parts plasma-tetracycline.
  • EXAMPLE TWELVE The proteins which constitute the matrix can be further modified by the addition of phospholipids.
  • reconstituted collagen and acidic phospholipids demonstrate together an enhanced uptake of calcium as compared to collagen matrixes without conjugated acidic phospholipids.
  • a 2.5 weight percent collagen dispersion at a pH of 5.0 to 5.5 was used for the addition of an acidic phospholipid, L-alpha-phosphatidic acid, dipalmitoyl, is added to the above reconstituted collagen dispersion at from .01 milligrams per milliliter collagen to 10 milligrams per milliliter collagen.
  • the conjugate dispersion is dehydrated at ambient temperatures and lyophilized.
  • activated protein particles, microcapsules, or demineralized bone matrix particles are added to the conjugate aqueous dispersion as described within this disclosure.
  • a reconstituted collagen matrix can be further modified by the addition of an alkaline source of calcium ions.
  • an alkaline source of calcium ions for example a reconstituted collagen dispersion with a collagen composition of 0.5 to 2.5 percent by weight and a pH of 5.0 to 5.5 is dialyzed against a saturated solution of calcium hydroxide in sterile distilled water saturated solution of calcium hydroxide in sterile distilled water.
  • the pH of the collagen dispersion reaches 10 to 10.5 the collagen dispersion is removed from the alkaline so ⁇ lution, placed in an appropriate sized mold and lyophilized to form a sponge.
  • collagen-calcium hydroxide conjugates demonstrate rapid release of the calcium and hydroxide ions and load only sufficient amounts of hydroxide ions to slightly adjust the pH.
  • EXAMPLE FOURTEEN A calcium hydroxide (CaOH) / collagen-gelatin microbead is fabricated using the following method.
  • a reconstituted collagen dispersion at neutral or acidic pH is made as described in prior Examples.
  • Powdered calcium hydroxide is slowly added to the dispersion until a pH such that a collagen to gelatin conversion was evident.
  • the pH necessary to effect this conversion is approximately 11.0 or above.
  • the visual effect at this conversion was quite noticable, as the collagen dispersion loses all its translucency and becomes opaque and chalky.
  • the colloidal dispersion can be formed into microbeads by immersion in an oil phase, as described in Example Three. Nevertheless, in this example, the collagen-CaOH gelatin dispersion may be dried by lyophilization at minus 40 minus 60 degrees centigrade. Dehydration at ambient temperatures also yields a solid mass.
  • This mass is milled and pulverized is into fine particles.
  • the particles are partially cross-linked in a .05 weight percent glutaraldehyde solution at a pH of 7.8.
  • the activated collagen/gelatin-CaOH particles are added to an alkaline collagen dispersion containing calcium hydroxide. This mixture may be lyophilized or dehydrated. However, activated demineralized bone particles may be added in a weight percent range of from 10 to 85 weight percent.
  • a collagen-calcium phosphate conjugate is derived as described by Cruz in U.S. Patent 3,767,437.
  • a recon ⁇ stituted collagen dispersion at a pH of 3.5 to 4.5 in sodium acetate is dialyzed first against 3 to 7 changes of deionized water and then dialyzed against a saturated solution of calcium hydroxide for 2 to 5 changes.
  • the collagen-CaOH solution is then dialyzed against a solution of phosphoric acid adjusted to pH 3.0 to 4.0.
  • the dialysis for 2 to 6 changes resulted in a Collagen-Calcium Phosphate conjugate.
  • the dispersion is lyophilized or dehydrated under an ambient conditions.
  • the resultant mass is pulverized under moderate force.
  • the resultant particles are sieved to a uniform particle size of 50 to 1000 millimicrons.
  • the particles are dried and placed in a .08 glutaraldehyde solution- also contains 8 mM calcium phosphate buffer.
  • the particles are filtered and rinsed once with sterile distilled water.
  • the partially crosslinked, activated particles are added to a reconstituted collagen dispersion with moderated mixing and agitation.
  • the dispersion can be left in a viscous gel-state, lyophilized, or dehydrated at ambient conditions.
  • the resultant dried mass has a diametrial tensile strength greater than one hundred PSI.
  • the inorganic particles are added so that no more than 20 weight percent of the entire conjugate is composed of the protein/inorganic particles.
  • the entire mass is cast and dehydrated as described in the above Examples
  • EXAMPLE EIGHTEEN Collagen-calcium phosphate particle conjugate derived from either hydroxyapatite or tricalcium phosphate particles even when crosslinking agents such as glutaraldehyde in low concentrations are added to the collagen matrix, demonstrate very low tensile strengths i.e., on the order of 30 psi or less.
  • a method is described in this example to provide collagen-hydroxyapatite or collagen-tricalcium phosphate conjugates with enhanced strength and reduced plucking of the inorganic particles from the matrix.
  • An acid dispersion of reconstituted collagen is made in the acid pH range using 0.05 acetic acid as described earlier.
  • the collagen dispersion is made at .75 weight percent collagen sheared in a Waring Blender and dialyzed against sterile isotonic saline until the pH of the dispersion reaches a range of 4.0 to 5.5.
  • Tricalcium phosphate particles medical grade and sterile with a parti ⁇ cle size of 50 to 150 millimicrons are added to the dispersion with moderate mixing.
  • the dispersion is degased under vacuum with moderate agitation.
  • the dispersion is placed in a dialysis tube and dialyzed against .01 molar phosphate buffer at pH 8.0.
  • the dialysis tube was period ⁇ ically removed aspetically and inverted several times to prevent separation of the mineral phase. After 24 to 48 hours of dialysis the dispersion is removed from the dialy ⁇ sis tubing, poured into a stainless steel mold and lyophilized at between minus 40 and minus 60°C.
  • the sponge like mass is cut into about .5 cm square cubes and milled carefully at low settings in an A-10 mill so as to provide a group of collagen-mineral particles on order of about 250 to 550 microns.
  • the particles are activated in a manner consistent with one of the embodiments of the invention. Specifically, in this example, the conjugate particles are immersed in a neutral buffered isotonic solution of bout 0.08 weight percent glutaraldehyde. The concentration of the glutaraldehyde was varied from .001 to .25 weight percent glutaraldehyde. The conjugate particles are activated for about 8 to 12 hours at 4 degree centigrade. The particles are removed by vacuum filtration and washed once in neutral buffered isotonic saline.
  • the activated protein-coated mineral particles are added to a reconstituted collagen dispersion of one to 2.5 percent by weight collagen, with a pH of from 3.5 to 5.0.
  • the activated particles are added to the dispersion in a weight range of from 25 to 85 percent by weight. The preferred range is from 40 to 75 percent by weight.
  • the activated protein-mineral particle/reconstituted collagen conjugate is poured into a stainless steel mold and dehy ⁇ drated at ambient temperatures with forced recirculated air.
  • the conjugate, once dehydrated may be lyophilized at minus 40 to minus 60°C.
  • Another conjugate of this type is cast except that prior to dehydration, a bioactive protein, peptide, or drug is added to the matrix, as has been described in earlier Examples.
  • EXAMPLE NINETEEN While a stable coating of reconstituted collagen can be formed in a continuous adherent layer on the surface of an inorganic particle a preferred method is to form multiple chelation links between the calcium, rich surface and the protein-based surface layer.
  • Particles of a calcium phosphate ceramic material namely tricalcium phosphate particles with a size of about 100 millimicrons are immersed in a 10 ppm solution of L-y-carboxyglutamic acid.
  • the particles are incubated in this solution for 24 to 48 hours 4°C.
  • the particles are removed from the solution dried under ambient conditions and immersed in about a 0.5 to 1 weight percent collagen dispersion containing about 10 to 50 ppm of L-y-carboxyglutamic acid.
  • the particles are agitated gently in this dispersion filtered from the dispersion then placed in a .15 molar NaCl solution containing .05 molar sodium phosphate buffer adjusted to pH 7.4 with dibasic and tribasic sodium phosphate.
  • the collagen coated particle is partially crosslinked in a .075 weight percent solution of glutaraldehyde for 8 to 10 hours.
  • the particles are removed from the glutaraldehyde solution by filtration then rinsed once in sterile saline solution.
  • Once activated some of these particles are used directly in osseous defects.
  • some of the activated particles are mixed into a 1 weight percent dispersion of reconstituted collagen.
  • the particles are mixed and agitated to assure a uniform dispersion.
  • the gel so obtained are used in certain osseous defects.
  • the collagen-particle dispersion was lyophilized or dehydrated under forced air under ambient conditions.
  • the resultant material is sterilized with ethylene oxide, gamma radiation, and/or by immersion in a .2 percent buffered glutaraldehyde solution.
  • the sodium salt of poly-L-glutamic acid or the random copolymer of L-glutamic acid may be used to coat the calcium phosphate particle prior to complexation with reconstituted collagen.
  • the particles are mixed and agitated within the polyamino acid solution, then under ambient conditions the particles are dehydrated or alternatively, lyophilized.
  • the coated particles are mixed in a reconstituted collagen dispersion and again dried to provide a uniform coating.
  • the coated particles so produced are partially crosslinked in .05 weight percent neutral buffered glutaraldehyde for about 10 to 12 hours at 4 °C.
  • the particles are vacuum filtered from the activating solution and dried.
  • the particles are then used as described within the embodiments of the invention.
  • the polyamino acid coated particles once dried may be added to a reconstituted collagen dispersion which contains about .05 to .1 weight percent glutaraldehyde.
  • the entire conjugate may be dehydrated or lyophilized, then milled to a powder if further complexation is intended.
  • EXAMPLE TWENTY-ONE System No. 2 of Example Seven described the fabrication of a reconstituted collagen/activated demineralized bone matrix conjugate with improved internal cohesive strength.
  • the weight percentage of activated particles is demonstrated to be useful in the range of 5 to 85 weight percent of the conjugate.
  • Nonactivated particles can be added to matrix in weight percent ranging from 0 to 95 percent of the total conjugate weight. If the non-activated or activated particles are inert, inorganic particles, specifically, tricalcium phosphate hydroxyapatite, their weight percent did not exceed 20 weight of the total conjugate mass.
  • EXAMPLE TWENTY-TWO Example Nine described a cohesive stress-bearing conjugate which is composed of an adhesive collagen-de ineralized powder which is hydrated and admixed with an additional 20 weight percent of activated demineralized bone particles. This composition is comprised of 30 weight percent original unactivated particles plus twenty weight percent activated demineralized bone particles (average particle size 150 microns) . The percentage of activated demineralized bone particles is from time to time, increased up to 50 weight percent of the total mass.
  • conjugates are admixed to contain up to 20 weight percent (with respect to the total conjugate mass) of activated or non-activated inert inorganic particles consisting of particles of tricalcium phosphate or hydroxyapatite with a particle size range of 20 to 750 millimicrons, with the preferred range being 20 to 150 millimicrons the total weight percent of particles of any type greater than 85 percent of the total mass.
  • activated or non-activated inert inorganic particles consisting of particles of tricalcium phosphate or hydroxyapatite with a particle size range of 20 to 750 millimicrons, with the preferred range being 20 to 150 millimicrons the total weight percent of particles of any type greater than 85 percent of the total mass.
  • the matrix component of the above examples may contain from a non-fibrillar collagen group, such as gelatin.
  • EXAMPLE TWENTY FOUR Polyamino acid microcapsules may be used to form protein-based, partially crosslinked particles as described in Example Three. The same procedure is followed except that a viscous solution of poly-1-lysine is used instead of gelatin. The other exception to the procedure is that the poly-L-lysine is used instead of gelatin. The other excep ⁇ tion to the procedure is that the poly-L-lysine is warmed only to 37 to 43 degrees centigrade.
  • EXAMPLE TWENTY-FIVE Other types of inorganic particles can be activated and reacted with collagen, gelatin, polyamino acid or polyalkenoic acids to form rigid, stress-bearing implants and cements.
  • Aluminosilicate glasses, which contain varying amounts of calcium fluoride, are used for stress-bearing cements and implantable bone replacement structures .
  • These hard-setting cements were formed from the reaction of powders and liquids. Specifically, milled aluminosilicate glass, designated G-309 or G-385 are provided.
  • the reactant liquid consists of from 35 to 55 percent polyacrylic acid, molecular weight from 15,000 to 60,000 and from 2 to 35 weight percent reconstituted collagen and the balance distilled, deionized water.
  • the powder and liquid are mixed at a powder to liquid ratio of from 1.4 to 3 grams per milliliter liquid.
  • the working time for the cement is about 1 minute 45 seconds to 2 minutes 45 seconds and the final set from 5 minutes 30 seconds to 6 minutes 45 seconds.
  • EXAMPLE TWENTY SIX The reconstituted collagen-glass ionomer cements are varied by the addition of from .01 to 3 percent glutaraldehyde into the liquid component as described in Example Twenty-Six. The inclusion of glutaraldehyde short ⁇ ens the working/setting time and produces a stronger cement as determined by physical testing.
  • EXAMPLE TWENTY SEVEN The reconstituted collagen-glass ionomer cements are varied by the addition of from .01 to 3 percent glutaraldehyde into the liquid component as described in Example Twenty-Six. The inclusion of glutaraldehyde short ⁇ ens the working/setting time and produces a stronger cement as determined by physical testing.
  • the liquid component as described in Examples Twenty-Five and Twenty Six can be further modified by the addition or substitution of polyamino acids for the polyalkenoic acids in. the liquid component.
  • the entire polyacid component of the liquid may be replaced with poly-L-glutamic acid.
  • from 5 to 45 weight percent of the liquid component may consist of a polyamino acid namely poly-L-glutamic acid.
  • Poly-L-asparatic acid, poly-L-lysine, homopolymers or random co-polymers of these or any polyamino acid may be added to the liquid component, combinations of these polyamino acids polymers vary the setting time and the ultimate physical strength of .the cement or implant.
  • TWENTY EIGHT Bone Morphogenetic Protein and/or bone proteins extracted from demineralized bone matrix may be incorporated into uniform unilamellar liposomes for controlled delivery to osseous defects.
  • the procedure for incorporation of the bioactive proteins onto and into the membrane bilayer is described below.
  • a phospholipid, l-palmitoyl-2-oleoyl-phosphatodyl- chlorine is dispersed in an agueous (sterile distilled water) phase by sonication and then mixed with lyophilized BMP such that the protein to lipid mass ratio to produce unilamellar BMP liposomes of optimal size (high encapsulation efficiency) is in the range of 1:2 to 1:3 with the optimal ratio being 1:2.5.
  • the resultant mixture is dried under nitrogen in a rotating flask.
  • the dried sample is then rehydrated in aqueous medium under nitrogen with gentle rotation of the flask.
  • the resulting unilamellar liposomes where separated from the free morphogenetic protein by chromatography through a b-4 or G200 Sephadex column.
  • the BMP-liposomes are stored at 4°C or alternatively, lyophilized. Prior to implantation reconstituted collagen sponges allogenic bone autogenous bone grafts or demineralized bone matrix can be soaked in the liposome preparation to stimulate osteogenesis. Alternatively, the BMP-liposomes can be mixed with an aqueous collagen dispersion for direct placement or injection to the wound site, or added to the matrix phase described in embodiments of this disclosure.
  • EXAMPLE TWENTY-NINE Bone morphogenetic protein and/or extracted bone proteins can be entrapped in the patient's own red blood cells by resealing the cell ghosts the presence of the bioactive proteins. This permits a highly biocompatible delivery system for BMP delivery to a wound site.
  • Fresh heparin-treated whole blood (about 50 milliliters) is centrifuged at 1000 gs for 10 minutes. The plasma and buffy coat is removed and the cells are washed three times in cold (4 degrees centigrade) Hanks Basic Salt Solution (HBSS) .
  • the packed cells are mixed rapidly with twice their volume of cold hemolysing solution consisting of distilled water containing approximately .5 milligram per milliliter BMP.
  • the encapsulated BMP/RBC conjugate may be pelleted and the pellet placed directly into an osseous defect.
  • the conjugate RBCs may be surface activated and partially crosslinked and incorporated into an osteogenic and/or stress-bearing implant.
  • Monoclonal antibodies, to bone tissue antigenic markers, may be attached to the surface of the cells so that the osteogenic proteins can be directed, parenterally, to an osseous defect to promote heating.
  • EXAMPLE THIRTY A method of Example Twenty such that a calcium binding protein or peptide is used to create a bond between the inorganic particle and the matrix.
  • a calcium binding peptide of molecular weight of 5,000 to 7,000. namely osteocalcin, which binds to hydroxyapatite may be used as the calcium binding interface in this method.
  • the particle is immersed in a 1 to 1000 ppm solution of osteocalcin prior to drying to affect this bound. The procedure in Example Twenty is then followed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Transplantation (AREA)
  • Public Health (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • General Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Botany (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Vascular Medicine (AREA)
  • Composite Materials (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Cardiology (AREA)
  • Materials Engineering (AREA)
  • Biophysics (AREA)
  • Urology & Nephrology (AREA)
  • Zoology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne des matériaux de réparation des os présentant une résistance cohésive et physique améliorée et utilisés dans des défauts induisant des efforts et des contraintes ou bien là où il est important de produire et maintenir la forme spécifique d'un implant. Le principe de création d'une interface et d'un conjugué stable entre une particule basée sur une protéine et une matrice organique s'applique également à des matériaux et des dispositifs d'apport de médicaments. Le produit comprend du collagène et des particules osseuses déminéralisées. Le produit peut contenir jusqu'au maximum 20 % en poids de matériaux inorganiques. Le produit peut être densifié par compression. Des facteurs, des mitogènes, des médicaments, des antibiotiques ostéogéniques supplémentaires peuvent être incorporés. Des matériaux inorganiques peuvent être liés à la matrice inorganique via un prérevêtement consistant en une protéine, un peptide ou un acide aminé de liaison du calcium ou de l'hydroxyapatite.
PCT/US1988/003932 1987-11-13 1988-11-14 Materiaux de reparation des os et administration de medicaments retardee WO1989004646A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11991687A 1987-11-13 1987-11-13
US119,916 1987-11-13

Publications (1)

Publication Number Publication Date
WO1989004646A1 true WO1989004646A1 (fr) 1989-06-01

Family

ID=22387166

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1988/003932 WO1989004646A1 (fr) 1987-11-13 1988-11-14 Materiaux de reparation des os et administration de medicaments retardee

Country Status (2)

Country Link
CA (1) CA1339083C (fr)
WO (1) WO1989004646A1 (fr)

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419275A1 (fr) * 1989-09-21 1991-03-27 Osteotech, Inc., Composition de poudre d'os fluide et déminéralisée et son utilisation pour la réparation de l'os
US5073373A (en) * 1989-09-21 1991-12-17 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
WO1992013565A1 (fr) * 1991-01-31 1992-08-20 Shaw, Robert, Francis Matrice contenant un facteur de croissance pour le traitement de lesions du cartilage
US5171579A (en) * 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
EP0530804A1 (fr) * 1991-09-06 1993-03-10 Shaw, Robert Francis Trousses et méthodes pour le traitement et pour la réparation des lésions ou des défauts de cartilage ou d'os
WO1993005823A1 (fr) * 1990-01-12 1993-04-01 Baylink David J Composition stimulant la croissance osseuse
EP0567391A1 (fr) * 1992-04-24 1993-10-27 Bristol-Myers Squibb Company Système biodégradable de délivrance de TGF-bêta pour la régénération osseuse
EP0605799A1 (fr) * 1992-12-18 1994-07-13 MERCK PATENT GmbH Endoprothèse creuse avec un remplissage favorisant la croissance osseuse
EP0585168A3 (en) * 1992-08-21 1994-08-17 Bristol Myers Squibb Co Composition and methods for the generation of bone
US5364839A (en) * 1990-06-18 1994-11-15 Genetics Institute, Inc. Osteoinductive pharmaceutical formulations
EP0621044A3 (fr) * 1993-04-21 1995-01-11 Sangi Kk Membranes de collagène.
AU672426B2 (en) * 1992-07-27 1996-10-03 Biomeasure, Inc. Neuromedin B receptor antagonists
WO1996039203A1 (fr) * 1995-06-06 1996-12-12 Gensci Regeneration Laboratories, Inc. Materiaux osteogeniques modifies
EP0709070A3 (fr) * 1994-10-25 1997-02-12 Osteonics Corp Eléments structuraux imbricables et méthode pour la réparation, l'augmentation et le remplacement des os
WO1997046178A1 (fr) * 1996-06-07 1997-12-11 Interpore International Biomateriaux poreux ameliores, et procedes de production associes
US5707962A (en) * 1994-09-28 1998-01-13 Gensci Regeneration Sciences Inc. Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof
WO1998014222A1 (fr) * 1996-09-30 1998-04-09 Children's Medical Center Corporation Procedes et compositions de programmation d'une matrice organique en vue d'un remodelage au sein d'un tissu cible
US5776193A (en) * 1995-10-16 1998-07-07 Orquest, Inc. Bone grafting matrix
US5904718A (en) * 1986-03-27 1999-05-18 Biocoll Laboratories, Inc. Delayed drug delivery system
WO2000045870A1 (fr) * 1999-02-04 2000-08-10 Sdgi Holdings, Inc. Compositions de pate osteogenique et leurs utilisations
WO2000045871A1 (fr) * 1999-02-04 2000-08-10 Sdgi Holdings, Inc. Compositions spongieuses osteogeniques extremement mineralisees et leurs utilisations
US6165487A (en) * 1996-09-30 2000-12-26 Children's Medical Center Corporation Methods and compositions for programming an organic matrix for remodeling into a target tissue
US6180606B1 (en) * 1994-09-28 2001-01-30 Gensci Orthobiologics, Inc. Compositions with enhanced osteogenic potential, methods for making the same and uses thereof
US6294187B1 (en) 1999-02-23 2001-09-25 Osteotech, Inc. Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
WO2002045623A1 (fr) * 2000-12-08 2002-06-13 Osteotech, Inc. Implant osseux pourvu d'un segment demineralise et son procede de fabrication
WO2001082993A3 (fr) * 1999-03-16 2002-07-18 Regeneration Tech Inc Implants pour applications orthopediques
WO2002009597A3 (fr) * 2000-08-01 2002-08-08 Regeneration Tech Inc Tenon cortical diaphysaire
WO2002067820A1 (fr) * 2001-02-23 2002-09-06 Smith & Nephew, Inc. Fabrication de substituts de greffe osseuse
US6492508B1 (en) 1996-06-03 2002-12-10 United States Surgical Corp. A Division Of Tyco Healthcare Group Nucleic acids encoding extracellular matrix proteins
US6569172B2 (en) 1996-08-30 2003-05-27 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6592599B2 (en) 1996-08-30 2003-07-15 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6696073B2 (en) * 1999-02-23 2004-02-24 Osteotech, Inc. Shaped load-bearing osteoimplant and methods of making same
EP1198236A4 (fr) * 1999-06-07 2004-04-07 Wright Medical Tech Inc Composition de substitut de greffe osseuse
WO2004060425A3 (fr) * 2002-12-27 2005-01-06 Angiotech Pharm Inc Compositions et procedes d'utilisation de collajolie
US6866668B2 (en) 1998-08-14 2005-03-15 Verigen Transplantation Service International (“VTSL”) AG Methods, instruments and materials for chondrocyte cell transplantation
US6902584B2 (en) 1995-10-16 2005-06-07 Depuy Spine, Inc. Bone grafting matrix
US7211266B2 (en) 2002-03-29 2007-05-01 Wright Medical Technology, Inc. Bone graft substitute composition
US7291179B2 (en) 2002-06-24 2007-11-06 Wright Medical Technology, Inc. Bone graft substitute composition
US7371409B2 (en) 2001-09-06 2008-05-13 Wright Medical Technology, Inc. Bone graft substitute composition
US7553810B2 (en) 2004-06-16 2009-06-30 Pneumrx, Inc. Lung volume reduction using glue composition
US7621954B2 (en) 2000-10-24 2009-11-24 Cryolife, Inc. In situ bioprosthetic filler and methods, particularly for in situ formation of vertebral disc bioprosthetics
US7722895B1 (en) 2004-09-20 2010-05-25 Warsaw Orthopedic, Inc. Osteogenic implants with combined implant materials, and materials and methods for same
US7887598B2 (en) 2002-06-13 2011-02-15 Kensey Nash Bvf Technology, Llc Devices and methods for treating defects in the tissue of a living being
US8133421B2 (en) 1999-02-23 2012-03-13 Warsaw Orthopedic, Inc. Methods of making shaped load-bearing osteoimplant
US8506646B2 (en) 2005-04-29 2013-08-13 Warsaw Orthopedic, Inc. Multi-purpose medical implant devices
US8652503B2 (en) 1997-03-13 2014-02-18 University Of Florida Research Foundation, Inc. Bone paste
US8690874B2 (en) 2000-12-22 2014-04-08 Zimmer Orthobiologics, Inc. Composition and process for bone growth and repair
US9101536B2 (en) 2002-08-06 2015-08-11 Matrix Medical Llc Biocompatible phase invertable proteinaceous compositions and methods for making and using the same
US9352003B1 (en) 2010-05-14 2016-05-31 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US9387094B2 (en) 2000-07-19 2016-07-12 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
US9393116B2 (en) 2003-06-11 2016-07-19 Warsaw Orthopedic, Inc. Osteoimplants and methods for their manufacture
US9757330B2 (en) 2013-10-18 2017-09-12 Industrial Technology Research Institute Recipe for in-situ gel, and implant, drug delivery system formed thereby
US10098981B2 (en) 2002-08-06 2018-10-16 Baxter International Inc. Biocompatible phase invertable proteinaceous compositions and methods for making and using the same
US10130736B1 (en) 2010-05-14 2018-11-20 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US10531957B2 (en) 2015-05-21 2020-01-14 Musculoskeletal Transplant Foundation Modified demineralized cortical bone fibers

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12311076B1 (en) 2018-06-07 2025-05-27 Seaspine, Inc. Demineralized bone matrix composition with enhanced osteoinductivity and osteoconductivity

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4291013A (en) * 1978-10-09 1981-09-22 Merck Patent Gesellschaft Mit Beschrankter Haftung Medicinally useful, shaped mass of collagen resorbable in the body
US4472840A (en) * 1981-09-21 1984-09-25 Jefferies Steven R Method of inducing osseous formation by implanting bone graft material
US4619989A (en) * 1981-05-05 1986-10-28 The Regents Of The University Of Cal. Bone morphogenetic protein composition
US4678470A (en) * 1985-05-29 1987-07-07 American Hospital Supply Corporation Bone-grafting material

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4291013A (en) * 1978-10-09 1981-09-22 Merck Patent Gesellschaft Mit Beschrankter Haftung Medicinally useful, shaped mass of collagen resorbable in the body
US4619989A (en) * 1981-05-05 1986-10-28 The Regents Of The University Of Cal. Bone morphogenetic protein composition
US4472840A (en) * 1981-09-21 1984-09-25 Jefferies Steven R Method of inducing osseous formation by implanting bone graft material
US4678470A (en) * 1985-05-29 1987-07-07 American Hospital Supply Corporation Bone-grafting material

Cited By (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5904718A (en) * 1986-03-27 1999-05-18 Biocoll Laboratories, Inc. Delayed drug delivery system
US5298254A (en) * 1989-09-21 1994-03-29 Osteotech, Inc. Shaped, swollen demineralized bone and its use in bone repair
US5073373A (en) * 1989-09-21 1991-12-17 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
US5439684A (en) * 1989-09-21 1995-08-08 Osteotech, Inc. Shaped, swollen demineralized bone and its use in bone repair
EP0419275A1 (fr) * 1989-09-21 1991-03-27 Osteotech, Inc., Composition de poudre d'os fluide et déminéralisée et son utilisation pour la réparation de l'os
US5290558A (en) * 1989-09-21 1994-03-01 Osteotech, Inc. Flowable demineralized bone powder composition and its use in bone repair
WO1993005823A1 (fr) * 1990-01-12 1993-04-01 Baylink David J Composition stimulant la croissance osseuse
US5364839A (en) * 1990-06-18 1994-11-15 Genetics Institute, Inc. Osteoinductive pharmaceutical formulations
WO1992013565A1 (fr) * 1991-01-31 1992-08-20 Shaw, Robert, Francis Matrice contenant un facteur de croissance pour le traitement de lesions du cartilage
US5368858A (en) * 1991-01-31 1994-11-29 Robert F. Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage
WO1993004710A3 (fr) * 1991-09-06 1993-04-15 Shaw Robert F Procedes et compositions destines au traitement et a la refection de breches ou de lesions dans le cartilage ou les os
US5270300A (en) * 1991-09-06 1993-12-14 Robert Francis Shaw Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone
EP0530804A1 (fr) * 1991-09-06 1993-03-10 Shaw, Robert Francis Trousses et méthodes pour le traitement et pour la réparation des lésions ou des défauts de cartilage ou d'os
US5171579A (en) * 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
EP0567391A1 (fr) * 1992-04-24 1993-10-27 Bristol-Myers Squibb Company Système biodégradable de délivrance de TGF-bêta pour la régénération osseuse
AU672426B2 (en) * 1992-07-27 1996-10-03 Biomeasure, Inc. Neuromedin B receptor antagonists
EP0585168A3 (en) * 1992-08-21 1994-08-17 Bristol Myers Squibb Co Composition and methods for the generation of bone
EP0605799A1 (fr) * 1992-12-18 1994-07-13 MERCK PATENT GmbH Endoprothèse creuse avec un remplissage favorisant la croissance osseuse
AU678211B2 (en) * 1993-04-21 1997-05-22 Kabushiki Kaisha Sangi Collagen membranes
EP0621044A3 (fr) * 1993-04-21 1995-01-11 Sangi Kk Membranes de collagène.
US6180606B1 (en) * 1994-09-28 2001-01-30 Gensci Orthobiologics, Inc. Compositions with enhanced osteogenic potential, methods for making the same and uses thereof
US5707962A (en) * 1994-09-28 1998-01-13 Gensci Regeneration Sciences Inc. Compositions with enhanced osteogenic potential, method for making the same and therapeutic uses thereof
US6180605B1 (en) * 1994-09-28 2001-01-30 Gensci Orthobiologics, Inc. Composition with enhanced osteogenic potential, method for making the same and therapeutic uses thereof
EP0709070A3 (fr) * 1994-10-25 1997-02-12 Osteonics Corp Eléments structuraux imbricables et méthode pour la réparation, l'augmentation et le remplacement des os
WO1996039203A1 (fr) * 1995-06-06 1996-12-12 Gensci Regeneration Laboratories, Inc. Materiaux osteogeniques modifies
US7842097B2 (en) 1995-10-16 2010-11-30 Depuy Spine, Inc. Tissue repair matrix
US6902584B2 (en) 1995-10-16 2005-06-07 Depuy Spine, Inc. Bone grafting matrix
US6764517B2 (en) 1995-10-16 2004-07-20 Depuy Acromed, Inc. Tissue repair matrix
US6187047B1 (en) 1995-10-16 2001-02-13 Orquest, Inc. Bone grafting matrix
US5776193A (en) * 1995-10-16 1998-07-07 Orquest, Inc. Bone grafting matrix
US6958223B2 (en) 1996-06-03 2005-10-25 United States Surgical Corporation Methods for producing extracellular matrix proteins
US6492508B1 (en) 1996-06-03 2002-12-10 United States Surgical Corp. A Division Of Tyco Healthcare Group Nucleic acids encoding extracellular matrix proteins
WO1997046178A1 (fr) * 1996-06-07 1997-12-11 Interpore International Biomateriaux poreux ameliores, et procedes de production associes
US7137989B2 (en) 1996-08-30 2006-11-21 Verigen Ag Method, instruments, and kit for autologous transplantation
US7048750B2 (en) 1996-08-30 2006-05-23 Verigen Ag Method, instruments, and kits for autologous transplantation
US6569172B2 (en) 1996-08-30 2003-05-27 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6592599B2 (en) 1996-08-30 2003-07-15 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6592598B2 (en) 1996-08-30 2003-07-15 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6599300B2 (en) 1996-08-30 2003-07-29 Verigen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
US6599301B2 (en) 1996-08-30 2003-07-29 Verrgen Transplantation Service International (Vtsi) Method, instruments, and kit for autologous transplantation
WO1998014222A1 (fr) * 1996-09-30 1998-04-09 Children's Medical Center Corporation Procedes et compositions de programmation d'une matrice organique en vue d'un remodelage au sein d'un tissu cible
US6165487A (en) * 1996-09-30 2000-12-26 Children's Medical Center Corporation Methods and compositions for programming an organic matrix for remodeling into a target tissue
US8652503B2 (en) 1997-03-13 2014-02-18 University Of Florida Research Foundation, Inc. Bone paste
US6866668B2 (en) 1998-08-14 2005-03-15 Verigen Transplantation Service International (“VTSL”) AG Methods, instruments and materials for chondrocyte cell transplantation
US7172629B2 (en) 1999-02-04 2007-02-06 Sdgi Holdings, Inc. Osteogenic paste compositions and uses thereof
WO2000045871A1 (fr) * 1999-02-04 2000-08-10 Sdgi Holdings, Inc. Compositions spongieuses osteogeniques extremement mineralisees et leurs utilisations
US8101676B2 (en) 1999-02-04 2012-01-24 Warsaw Orthopedic, Inc. Osteogenic paste compositions and uses thereof
US7563455B2 (en) 1999-02-04 2009-07-21 Warsaw Orthopedic, Inc. Highly-mineralized osteogenic sponge compositions, and uses thereof
WO2000045870A1 (fr) * 1999-02-04 2000-08-10 Sdgi Holdings, Inc. Compositions de pate osteogenique et leurs utilisations
US8147862B2 (en) 1999-02-04 2012-04-03 Warsaw Orthopedic, Inc. Highly mineralized osteogenic sponge compositions and uses thereof
US8399010B2 (en) 1999-02-04 2013-03-19 Warsaw Orthopedic, Inc. Highly-mineralized osteogenic sponge compositions and uses thereof
US6696073B2 (en) * 1999-02-23 2004-02-24 Osteotech, Inc. Shaped load-bearing osteoimplant and methods of making same
US6294187B1 (en) 1999-02-23 2001-09-25 Osteotech, Inc. Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
US8133421B2 (en) 1999-02-23 2012-03-13 Warsaw Orthopedic, Inc. Methods of making shaped load-bearing osteoimplant
WO2001082993A3 (fr) * 1999-03-16 2002-07-18 Regeneration Tech Inc Implants pour applications orthopediques
EP1198236A4 (fr) * 1999-06-07 2004-04-07 Wright Medical Tech Inc Composition de substitut de greffe osseuse
US7371410B2 (en) 1999-06-07 2008-05-13 Wright Medical Technology, Inc. Bone graft substitute composition
US7371408B1 (en) 1999-06-07 2008-05-13 Wright Medical Technology, Inc. Bone graft substitute composition
US9999520B2 (en) 2000-07-19 2018-06-19 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
US9387094B2 (en) 2000-07-19 2016-07-12 Warsaw Orthopedic, Inc. Osteoimplant and method of making same
WO2002009597A3 (fr) * 2000-08-01 2002-08-08 Regeneration Tech Inc Tenon cortical diaphysaire
US7896920B2 (en) 2000-10-24 2011-03-01 Cryolife, Inc. In situ bioprosthetic filler and method, particularly for the in situ formation of vertebral disc bioprosthetics
US7621954B2 (en) 2000-10-24 2009-11-24 Cryolife, Inc. In situ bioprosthetic filler and methods, particularly for in situ formation of vertebral disc bioprosthetics
US7621959B2 (en) * 2000-10-24 2009-11-24 Cryolife, Inc. Methods for the in situ formation of a bioprosthetic device, particularly vertebral disc bioprosthetics
WO2002045623A1 (fr) * 2000-12-08 2002-06-13 Osteotech, Inc. Implant osseux pourvu d'un segment demineralise et son procede de fabrication
US8690874B2 (en) 2000-12-22 2014-04-08 Zimmer Orthobiologics, Inc. Composition and process for bone growth and repair
WO2002067820A1 (fr) * 2001-02-23 2002-09-06 Smith & Nephew, Inc. Fabrication de substituts de greffe osseuse
US7371409B2 (en) 2001-09-06 2008-05-13 Wright Medical Technology, Inc. Bone graft substitute composition
US8968465B2 (en) 2002-03-29 2015-03-03 Wright Medical Technology, Inc. Bone graft substitute composition
US7211266B2 (en) 2002-03-29 2007-05-01 Wright Medical Technology, Inc. Bone graft substitute composition
US8657952B2 (en) 2002-03-29 2014-02-25 Wright Medical Technology, Inc. Bone graft substitute composition
US8163032B2 (en) 2002-06-13 2012-04-24 Kensey Nash Bvf Technology, Llc Devices and methods for treating defects in the tissue of a living being
US7892291B2 (en) 2002-06-13 2011-02-22 Kensey Nash Bvf Technology, Llc Devices and methods for treating defects in the tissue of a living being
US8419802B2 (en) 2002-06-13 2013-04-16 Kensey Nash Bvf Technology, Llc Devices and methods for treating defects in the tissue of a living being
US7887598B2 (en) 2002-06-13 2011-02-15 Kensey Nash Bvf Technology, Llc Devices and methods for treating defects in the tissue of a living being
US9283074B2 (en) 2002-06-13 2016-03-15 Kensey Nash Bvf Technology, Llc Devices and methods for treating defects in the tissue of a living being
US7291179B2 (en) 2002-06-24 2007-11-06 Wright Medical Technology, Inc. Bone graft substitute composition
US7658768B2 (en) 2002-06-24 2010-02-09 Wright Medical Technology, Inc. Bone graft substitute composition
US10398801B2 (en) 2002-08-06 2019-09-03 Baxter International Inc. Biocompatible phase invertable proteinaceous compositions and methods for making and using the same
US10098981B2 (en) 2002-08-06 2018-10-16 Baxter International Inc. Biocompatible phase invertable proteinaceous compositions and methods for making and using the same
US9101536B2 (en) 2002-08-06 2015-08-11 Matrix Medical Llc Biocompatible phase invertable proteinaceous compositions and methods for making and using the same
WO2004060425A3 (fr) * 2002-12-27 2005-01-06 Angiotech Pharm Inc Compositions et procedes d'utilisation de collajolie
US9393116B2 (en) 2003-06-11 2016-07-19 Warsaw Orthopedic, Inc. Osteoimplants and methods for their manufacture
US7553810B2 (en) 2004-06-16 2009-06-30 Pneumrx, Inc. Lung volume reduction using glue composition
US7722895B1 (en) 2004-09-20 2010-05-25 Warsaw Orthopedic, Inc. Osteogenic implants with combined implant materials, and materials and methods for same
US8148329B2 (en) 2004-09-20 2012-04-03 Warsaw Orthopedic, Inc. Osteogenic implants with combined implant materials and methods for same
US8092823B2 (en) 2004-09-20 2012-01-10 Warsaw Orthopedic, Inc. Osteogenic implants with combined implant materials and methods for same
US8470354B2 (en) 2004-09-20 2013-06-25 Warsaw Orthopedic, Inc. Osteogenic implants with combined implant materials and methods for same
US8506646B2 (en) 2005-04-29 2013-08-13 Warsaw Orthopedic, Inc. Multi-purpose medical implant devices
US9352003B1 (en) 2010-05-14 2016-05-31 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US10130736B1 (en) 2010-05-14 2018-11-20 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US11305035B2 (en) 2010-05-14 2022-04-19 Musculoskeletal Transplant Foundatiaon Tissue-derived tissuegenic implants, and methods of fabricating and using same
US9757330B2 (en) 2013-10-18 2017-09-12 Industrial Technology Research Institute Recipe for in-situ gel, and implant, drug delivery system formed thereby
US10531957B2 (en) 2015-05-21 2020-01-14 Musculoskeletal Transplant Foundation Modified demineralized cortical bone fibers
US11596517B2 (en) 2015-05-21 2023-03-07 Musculoskeletal Transplant Foundation Modified demineralized cortical bone fibers
US12295848B2 (en) 2015-05-21 2025-05-13 Musculoskeletal Transplant Foundation Implants including modified demineralized cortical bone fibers and methods of making same

Also Published As

Publication number Publication date
CA1339083C (fr) 1997-07-29

Similar Documents

Publication Publication Date Title
US5904718A (en) Delayed drug delivery system
CA1339083C (fr) Substance pour reparation osseuse et systeme d'administration-retard de medicament
US6311690B1 (en) Bone repair material and delayed drug delivery system
EP0851772A1 (fr) Materiaux osteogeniques modifies
US4394370A (en) Bone graft material for osseous defects and method of making same
US4472840A (en) Method of inducing osseous formation by implanting bone graft material
US6180606B1 (en) Compositions with enhanced osteogenic potential, methods for making the same and uses thereof
EP0883410B1 (fr) Dispositif osteogenique et son procede de preparation
AU770196B2 (en) Osteogenic paste compositions and uses thereof
Woo et al. Enhancement of bone growth by sustained delivery of recombinant human bone morphogenetic protein-2 in a polymeric matrix
US6180605B1 (en) Composition with enhanced osteogenic potential, method for making the same and therapeutic uses thereof
Bessa et al. Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery)
US4975526A (en) Bone collagen matrix for zenogenic implants
US5162114A (en) Bone collagen matrix for xenogenic implants
US5133755A (en) Method and apparatus for diodegradable, osteogenic, bone graft substitute device
AU782394B2 (en) Compositions and methods for forming and strengthening bone
US5273964A (en) Inorganic and organic composition for treatment of bone lesions
Ono et al. Bone induction of hydroxyapatite combined with bone morphogenetic protein and covered with periosteum
Miller et al. The induction of bone by an osteogenic protein and the conduction of bone by porous hydroxyapatite: a laboratory study in the rabbit
US20010014667A1 (en) Compositions with enhanced osteogenic potential, methods for making the same and therapeutic uses thereof
US20020128722A1 (en) Bone repair material and delayed drug delivery system
Song et al. Bone morphogenetic protein-2 sustained delivery by hydrogels with microspheres repairs rabbit mandibular defects
KR20210145130A (ko) 프롤린-풍부 펩타이드를 포함하는 개선된 뼈 임플란트 매트릭스 및 그것의 제조 방법
Chen et al. Preparation and biological characteristics of recombinant human bone morphogenetic protein-2-loaded dextran-co-gelatin hydrogel microspheres, in vitro and in vivo studies
Clokie Collagen and a thermally reversible poloxamer deliver demineralized bone matrix (DBM) and biologically active proteins to sites of bone regeneration

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE